1. Field of the Invention
The present invention relates to novel 1,2-benzoquinones, methods of preparation of 1,2-benzoquinones, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more of such benzoquinones.
2. Background Art
The quinone moiety occurs abundantly in nature playing vital roles in normal biochemical processes and in the action of many cytotoxins. See, e.g., P. J. O'Brien, Molecular mechanisms of quinone cytotoxicity, Chem.-Biol. Interactions, 80:1-41 (1991); H. Nohlet al., Quinones in biology: Functions in electron transfer and oxygen activation, Adv. Free Rad. Biol. Med., 2:211-279 (1986); W. Kersten, Inhibition of RNA synthesis by quinone antibiotics, Prog. Mol. Subcell. Biol., 2:48-57 (1971); C. Olenick et al., Bactericidal action of a 2-hydroxy-3-alkyl-1,4 naphthoquinone, Ann. N.Y. Acad. Sci., 235:542-552 (1974); S. Rich, In: Fungicities, An Advanced Treatise, Torgeson, D. C., Ed.; Academic Press: New York, 1968; Y. Martin et al., Relationship between physical properties and antimalarial activities of 1,4-naphthoquinone, J. Med. Chem., 16:1089-1093 (1973); T. Eisner et al., Defense mechanisms of anthropoids, 57, Chemistry of defensive secretions of bombardier beetles, J. Insect. Physiol., 23:1383-1386 (1977); J. Driscoll et al., Structure-antitumor activity relations among quinone derivatives, Cancer Chemother. Rep., 4(part 2):1-27 (1974); and G. Powis, Free radical formation by antitumor quinones, Free Rad. Biol. Med., 6:63-101 (1989).
More than 1000 naturally occurring quinones have been tested for antitumor activity several of these including doxorubicin, daunorubicin and mitomycin C are in current clinical use. Aziridinyl-1,4-benzoquinones were among the earliest rationally designed synthetic anticancer agents. G. Powis, Metabolism and reactions of quinoid anticancer agents, Pharmacol. Ther., 35:57-162 (1987); and T. Deeley, A clinical trial of synkavit in the treatment of carcinoma of the bronchus, Br. J. Cancer, 16:387-389 (1980). Of these, diaziquinone 3,6-bis(ethylcarboxyamino)-2,5-diaziridinyl-1,4-benzoquinone AZQ; NSC-182986! is currently in clinical use primarily for treatment of brain tumors.
Relative to 1,4-benzoquinone derivatives, the 1,2-benzoquinone derivatives have been reported to be much more difficult to prepare even in moderate yield. Indeed, there has been little exploration of 1,2-benzoquinone compounds despite the potential for 1,2-benzoquinones to form highly reactive species that could crosslink DNA and thus have potential as antitumor agents.
It thus would be desirable to have improved means for obtaining 1,2-benzoquinone compounds. It also would be desirable to have new 1,2-benzoquinone compounds, particularly 1,2-benzoquinone compounds that are useful as antitumor agents.